Mechanisms of retrovirus-induced brain pathogenesis have been studied using a murine polytropic retrovirus model where two closely related viruses differing in virulence were compared. Clinical brain disease was correlated with an increase in expression of several cytokines and beta-chemokines including TNF-alpha, TNF-beta, interleukin-1alpha, MIP-1alpha, MIP-1beta, MCP-1, IP-10 and RANTES. The increased expression of these genes occurred prior to clinical disease suggesting that they might be involved in induction of the pathogenic process. Two separate regions of the viral envelope gene were associated with disease in this model, but upregulation of cytokines and chemokines was associated with only one of these regions. The mechanism of action of the other region remains unknown, but may provide an opportunity to detect new pathogenic mechanisms of retrovirus-induced brain disease.